Our objective is to further our understanding of the structure and functions of the voltage-gated sodium channel, and the organization of the sodium and potassium channels. It is to be attained by the judicious use of analogues of tetrodotoxin (TTX) and saxitoxin (STX) as molecular probes in electrophysiological studies on living excitable membranes. From past work done on this project, the TTX/STX binding site is believed to be on the outside surface of the excitable membrane, very close to the external orifice of the sodium channel. The active groups of the TTX and STX molecules, which are otherwise quite different, have been identified. A probable conformation these molecules assume in blocking the channel has been proposed. Insights gained from the past structure-activity studies will be used towards attempts to locate the TTX/STX binding site, by developing jointly with long-time collaborating bioorganic chemists, possible covalent compounds for the binding site. Also, by studying the actions of several available analogues of TTX and STX, refinements of the surface-receptor hypothesis will be made which could help in probing the structure of the toxin binding site. Chiriquitoxin, an analogue of TTX, has been shown to block the sodium channel, and also to affect some aspects of the potassium channel. This toxin will be studied in detail, with the aim of finding a possible spatial relation to the distribution of the sodium and potassium channels.